8-arylpurine derivatives and process of preparing same



Patented Feb. 10, 1953 UNITED STATES ATENT OFFICE S-ARYLPURINE DERIVATIVES AND PROCESS OF PREPARING SAME George H. Hitchings, Tuckahoe, and Gertrude B. Elion, Bronxville, N. Y., assignors to Burroughs Wellcome & 00. (U. S. A.) Inc., Tuckaho'e, N. Y., a corporation of New York No Drawing. Application February 15, 1950, Serial No. 144,395

12 Claims.

where M is an aryl radical of not more than 2 rings, Z is a substituent selected from the class consisting of chlorine, bromine, hydroxyl, amino, hydrazino, thiol, alkylthio and substituted amino of the type where R1 is a radical selected from the group consisting of hydrogen, lower alkyl and aryl and R2 is a lower alkyl radical and R1 and R2 together may represent the components of a cyclic system, and where X is a radical selected from the class consisting of hydrogen, amino, chlorine, bromine, lower alkyl and alkoxyl and Y is selected from the class consisting of hydrogen, amino, chlorine, bromine, lower alkyl and alkoxyl, carboxy, carbalkoxy and carbamido radicals.

The processes of the present invention involve the preliminary preparation of an amide of a 2,4,5-triaminopyrimidine with subsequent ring closure to form the purine. The amide may be prepared by treatment of the pyrimidine, or a suitable acid salt of the pyrimidine with the acid chloride in the presence of an alkali. The ring closure of the benzamidopyrimidine to the purine may be effected simply by heating the compound to its melting point, and this is indeed the preferred procedure in many instances. In other instances it is preferred to heat the amide with phosphorylchloride. In the case of 5-benz- 'amido-2,4-diamino-6-hydroxy-pyrimidines this result in ring closure to the purine and simultaneous chlorination resulting in a 2-amino-6- chloro-8-phenylpurine. The fi-chloropurine so ,formed is capable of transformation in a variety of ways. It may be replaced by other groups by treatment of the reactive chlorocompounds with ammonia, amines, alkali hydrosulfide, or by hydrolysis the hydroxyl group may be restored to this position.

The following examples serve to illustrate the teachings of the present invention, but are not intended in any way to limit the invention, the scope of which is defined in the claims.

- EXAMPLE 1 2,6-diamino-8-p-chlorophenylpurine 37.5 g. of 2,4,5,6-tetraminopyrimidine sulfite was dissolved in 200 ml. of 1 N sodium hydroxide. To this solution was added alternately, with continued stirring, ml. of 2 N sodium hydroxide and 36.4 g. of p-chlorobenzoyl chloride. the pH of the solution being kept between 8 and 9 and the temperature between 10 20 throughout the reaction. The reaction mixture was allowed to stand at 4 overnight and the precipitate filtered 01f, washed with water, alcohol and ether and dried at 100. The yield was 36 g. of 2,4,6-triamino-5-p-chlorobenzamido pyrimidine.

8.2 g. of 2,4,6-triamino-5-p-chlorobenzamido pyrimidine was heated for 1 hour at 260-270. Water vapor was given ofi and the solid turned dark. After cooling, the solid was dissolved in 500 ml. of 0.2 N sodium hydroxide, filtered and the filtrate acidified to pH 5 with glacial acetic acid. The precipitate was collected by centrifugation, washed with water, alcohol and. ether and boiled with 4 liters of 1 N hydrochloric acid. The acid solution was filtered hot and brought to pH 5 by addition of sodium hydroxide. 3.9 g. of 2,6-diamino-8-chloropheny1 purine basic by:- drochloride were obtained on cooling.

EXAMPLE 2 2,6-dz'amz'no-8-o-chlorophenylpurine 2,4,6-triamino-5 o chlorobenzamido pyrimidine was prepared from 2,4,5,6-tetraaminopyrimidine ulfite and o-chlorobenzoyl chloride in the same manner as described in Example 1 for the corresponding p-chloro derivative.

12 g. of 2,4,6-triam'ino-5-o-chlorobenzamido pyrimidine was heated at 250-260 for 1 hour. The residue was dissolved in 500 ml. of 1 N sodium hydroxide, filtered and the filtrate acidified to pH 5 with acetic acid. The precipitate was collected by centrifugation, washed with water, alcohol and ether and dried at The precipitate was boiled with 1,500 ml. of 1 N hydrochloric acid, a small amount of insoluble material filtered off and the hot acid filtrate brought heated at 240 for 30 minutes.

to pH 5 by the addition of saturated sodium hydroxide solution. After cooling to 4, the yellow precipitate wa collected, washed and dried at 110. The yield was 6 g. of 2,6-diamino-8-ochlorophenyl purine basic hydrochloride.

EXAMPLE 3 2,6-dz'amz'no-8-m-chlorophenylpurine 8.3 g. of 2,4,6-triamino-5-m-chlorobenzamidopyrimidine, prepared in the usual manner, was heated at 270-280 for 1 hour. The molten solid, after cooling, was dissolved in 250 ml. of 1 N sodium hydroxide and the alkaline solution filtered into 2 liters of boiling 1 N hydrochloric acid. The acid solution was filtered hot to remove an insoluble residue and the hot filtrate brought to pH 5 by the addition of saturated sodium hydroxide solution. After cooling, the precipitate of 2,6-diamino-8-m-ehlorophenylpurine basic hydrochloride was filtered ofi, washed with water, alcohol and ether and dried at 110; the yield was 2.8 g.

EXAMPLE 4 2,6-dimiino-8-nitrophenylpurine 10.85 g. of crude 2,4,6-triamino-5-p-nitrobenzamidopyrimidine, prepared in the usual manner, was heated at 260 for 45 minutes. The residue leached with 100 ml. of acetone to remove any p-nitrobenzoic acid contaminant, air dried, then treated with 500 ml. of 0.05 N sodium hydroxide solution. An insoluble residue was filtered off and the alkaline filtrate poured slowly into 500 ml. hot water containing 25 ml. of glacial acetic acid. The orange precipitate, after cooling, was collected by centrifugation, washed with water alcohol and ether and dried at 110; yield 4.95 g. of 2,6-diamino-8-p nitrophenylpurine hydrate.

EXAMPLE 5 2,6-dz'amino-8-p-nitrophenylpurine 16 g. of 2,4,6-triamino-5-p-nitrobenzamidopyrimidine was refluxed with 375 ml. of phosphorus oxychloride for 10 hours. The reaction mixture was taken down almost to dryness on the steam bath under reduced pressure and the residue decomposed with 500 g. of ice. The precipitate was filtered off, dissolved in 600 ml. of 0.05 N sodium hydroxide and the alkaline solution filtered into 400 ml. of hot water containing 25 ml. of glacial aceticacid. After cooling the orange precipitate was collected by centrifugation, washed with water, alcohol and dried at 110. The yield was 7.85 g. of 2,6- diamino-8-p-nitrophenylpurine hydrate.

EXAMPLE 6 2,6-dz'amino-8-m-nitrophenylpurine g. of 2,4,6-triamino-5-m-nitrobenzamidopyrimidine, prepared in the usual manner, was The residue was cooled, dissolved in 600 ml. of 0.3 N sodium hydroxide and the alkaline solution filtered into 300 ml. of hot water containing 50 ml. of glacial acetic acid. After cooling, the precipitate was filtered off, boiled with 3 liters of 1 N hydrochloric acid. The acid solution was filtered hot, and 3 g. of 2,6-diamino-8-m-nitrophenylpurine hydrochloride hydrate were filtered 01f after chilling. Another 1.9 g. of the purine, in the form of the basic hydrochloride, was recovered from the acid filtrate by adjusting the pH to 5 with sodium hydroxide.

4 EXAMPLE '1 2,6 -diamino-8-p-carbomethoxyph enylpurine 9.3 g. of 2,4,6-triamino-5-p-carbomethoxybenzamidopyrimidine, prepared from 2,4,5,6- tetraaminopyrimidine dihydrochloride and pcarbomethoxybenzoylchloride in the usual manner, was heated at 260-270 for 1 hour. The dark residue was treated with 600 ml. of 0.5 N sodium hydroxide and the alkaline solution filtered into 300 ml. of hot water containing 50 ml. of glacial acetic acid. The brown precipitate was collected by centrifugation, redissolved in 350 ml. of 0.3 N sodium hydroxide and filtered into 500 ml. of boiling water containing ml. of concentrated hydrochloric acid. The acid solution was filtered hot and the filtrate allowed to cool overnight. The yellow precipitate of 2,6- diamino-8-p-carbomethoxyphenylpurine hydrochloride hydrate weighed 2.5 g. after filtration, washing and drying at On adjustment of the pH to 5, another 1.8 g. of this purine in the form of the basic hydrochloride was isolated.

EXAMPLE 8 2,6-dz'amino-8-p-metho:z:yphenylpurine 8 g. of 2,4,6-triamino-5-p-methoxybenzamidopyrimidine prepared in the usual manner, was refluxed with 250 ml. of phosphorus oxychloride for 4 hours. The reaction mixture was taken to dryness under reduced pressure and the residue mixed with 300 g. of ice. The precipitate was filtered off, dissolved in 200 ml. of 0.5 N sodium hydroxide and the alkaline solution filtered into 300 ml. of hot water containing 25 ml. of glacial acetic acid. The precipitate was collected after cooling, washed with water, alcohol and ether, and dried at The yield of crude 2,6-diamino-8-p-methoxyphenylpurine was 5.7 g. This crude material contained some bound phosphorus. However, after boiling with 2 N hydrochloric acid for 30 minutes and subsequent recrystallization from 1 N hydrochloric acid, the phosphorus was removed.

EXAMPLE 9 2,6-diamino-8-m-bromophenylpurine 10 g. of 2,4,6-triamino-5-m-bromobenzamidopyrimidine, prepared in the usual manner, was refluxed with 250 ml. of phosphorus oxychloride 'for 8 hours. The reaction mixture was taken to dryness under reduced pressure, treated with 300 g. of crushed ice and the precipitate collected by filtration. Theprecipitate was dissolved in 375 ml. of 0.4 N sodium hydroxide, the alkaline solution filtered and the filtrate brought to pH 5 by the addition of glacial acetic acid. After centrifugation, washing and drying at 110, the precipitate of crude 2,6-diamino-8-m-bromophenylpurine weighed 9.5 g.

EXAMPLE 10 2,6-dz'amz'no-8-phenylpurine 2 g. of 2,4,6-triamino-5-benzamidopyrimidine, prepared in the usual manner, was refluxed for 3 hours with 100 ml. of phosphorusoxychloride. The mixture was taken to dryness under reduced pressure and the residue treated with 100 ml. of ice water. After the mixture had been made alkaline by the addition of concentrated ammonium hydroxide, the solution was filtered and the filtrate adjusted to pH 5 with acetic acid. The'precipitate was filtered off'and purified twice more by solution in dilute ammonium hydroxide and precipitation at pH 5 with acetic acid; yield, 1.5 g. of 2,6-diamino-S-phenylpurine.

EXAMPLE 11 2,6-dz'amino-8-(3',5'-dinitrophenyl) purine 10 g. of 2,4,6-triamino-5 (3,5-dinitrobenzamido) pyrimidine, prepared in the usual manner, was refluxed for 8 hours with 250 ml. of phosphorus oxychloride. After cooling the reaction mixture was filtered and the insoluble residue treated with 350 g. of ice. The precipitate was collected by filtration and, after recrystallization from 1 liter of 1 N hydrochloric acid, gave 2 g. of 2,6-diamino-8-(3',5'-dinitrophenyl) purine hydrochloride and, on adjustment of the pH of this acid filtrate to 5, another 0.5 g. of the basic hydrochloride of the same purine.

EXAMPLE 12 2,6-diamino-8-5-naphthylpurine 8.25 g. 2,4,6-triamino-5-/3-naphthoylaminopyrimidine, prepared from 2,4,5,6-tetraaminopyrimidine hydrochloride and B-naphthoylchloride, was heated at 250 for 1 /2 hours. The residue was dissolved in 300 ml. of 0.6 N sodium hydroxide, filtered and the filtrate poured into 200 ml. of dilute acetic acid. After cooling, filtration and drying at 110, the yield of 2,6-diamino-8- fi-naphthylpurine was 4.5 g.

EXAMPLE 13 2-amino-6-hydroxy-8-phenylpurine 29.2 g. of 2,4,5-triamino-6-hydroxypyrimidine sulfite was dissolved in 100 ml. of water and 80 ml. of 2 N sodium hydroxide. To this solution, kept at l-15, were added alternately, with stirring, 80 ml. of 2 N sodium hydroxide and 22.6 g. of benzoylchloride, the pH being kept at ca. 8

' throughout. After standing overnight at 4, the

mixture was brought to pH 6 by addition of acetic acid and the precipitate collected, washed with water, alcohol and ether and dried at 100. The yield was 19 g. cf 2,-diamino--benzamido-6- hydroxypyrimidine.

5 g. of 2,4-diamino-E-benzamido-G-hydroxypyrimidine was mixed in a mortar with 3 g. of benzamide and the mixture heated at 280300 for 30 minutes. After cooling, the mixture was leached with 100 ml. of ether and the insoluble residue then dissolved in 350 ml. of 0.3 N sodium hydroxide. The alkaline solution was filtered and acidified to pH 5 with acetic acid. The precipitate was collected by filtration,. boiled with 700 ml. of 1.2 N hydrochloric acid, and the acid solution filtered hot. On neutralization to pH 5 with sodium hydroxide and cooling, 1.85 g. of 2- amino-B-hydroxy-B-phenylpurine was collected.

EXAMPLE 14 Z-amz'no-6-chZoro8-phenylpurine and drying at 100 the precipitate of 2-amino-6- chloro-B-phenylpurine hydrate weighed 8.25 g.

6 EXAMPLE 15 Z-amz'no-6-hydrory-8-phenylpurine l g. of crude 2-amino-6-chloro-8-phenylpurine hydrate was refluxed for 1 hour with 40 ml. of 2 N hydrochloric acid. After cooling, the precipitate was collected, washed with water, alcohol and ether and dried at 120. The product, which was identified as 2-amino-6-hydroxy-8-phenylpurine hydrochloride, weighed 0.7 g.

EXAMPLE 16 2-amino-6-hydroxy-8-p-nitrophenylpurine 8.4 g. of 2,4-diamino-5-p-nitrobenzamido-6- hydroxypyrimidine, prepared in the usual manner, was mixed with 9 g. of p-nitrobenzamide and the mixture heated at 300 for 1 hour. The residue was cooled, leached with 200 ml. of ether and dissolved in 1 liter of 0.2 N sodium hydroxide. The alkaline solution was filtered, brought to pH 5 with acetic acid and the precipitate collected by centrifugation. After washing with water, alcohol and ether, the precipitate of 2-amino-6- hydroxy-8-p-nitrophenylpurine weighed 3.0 g.

EXAMPLE 1'? 2-amin0-6-chZoro-8-p-chlorophenylpurine 18.2 g. of 2,4,5-trlamino-6-hydroxypyrimidine sulfite wa dissolved in 25 ml. of 2 N sodium hydroxide. To this solution, kept at l0-l5 were added alternately, with stirring 25 ml. of 2 N sodium hydroxide and 17.5 g. of p-chlorobenzoylchloride, the pH being kept at 7-8. After standing overnight, the mixture was acidified to pH 5 and the product filtered off, washed and dried. The yield of 2A-diamino-6-hydroxy-5-p chlorobenzamidopyrimidine Was 14.7 g.

10 g. of 2,4-diamino-5-p-chlorobenzamido-6- hydroxypyrimidine, prepared in the above manner, was refluxed with 200 ml. of phosphorus oxychloride for 2 hours. The solution was taken to dryness under reduced pressure and the residue poured into 300 g. of ice. After-the precipitate was collected it was treated with 300 ml. of water and 50 ml. of 2 N sodium hydroxide. The alkaliinsoluble portion was filtered off and the alkaline filtrate acidified to pH 5 with acetic acid. The pale yellow precipitate after filtration, washing with water and drying at consisted of 7.1 g. of 2t-amino-6-chlcro-8-p-chlorophenylpurine hyra e.

EXAMPLE 18 Z-amino-6-p-chloroanilino-8- p-chlorophenylpurine 1.2 g. of 2-amino-6-chloro-8-p-chlorophenylpurine, prepared as above, was heated with 1.4

To 0.85 g. of 2-amino-6-chloro-8-p-chlorophenylpurine were added 2 ml. of n-butylamine, 0.1 ml. of concentrated hydrochloric acid and 5 m1. of absolute ethanol. The mixture was. .1?-

at 120" for three hours.

action mixture was filtered and theicrude prefate.

fiuxed for 30 minutesiandathen evaporated almost todryness on a steam bath. The residue was diluted to"100'ml. with'water, ma'de' strongly acidic wi th hydrochloric .acid and. .the. insoluble yellow residue 'filtered'.off, washed-with water, alcohoh'anddried at 120. L'Ihe yield of Z-ami- "no- 6-n-bi-itylamino 8-p-chlorophenylpurine was 4.9 g. of 2,4-diamind -b'enzamido6-hydroxypyrimidine was dissolved in 'ml.-: of ZTZN. sodium hydroxide and the. solution taken to dryness'on the steam bathunder reduced pressure. 'Ihe; sodiu m-sa1t thus obtained was heated 'at 280-for 1--hour. W'ater-was given ofiand the solid turned dark. .After cooling, the residue wasdissolved in 400 ml. of water containing 10 -ml. of 2 'Nsodium hydroxide. The alkaline solution was filtered andacidified with acetic. acid. The precipitateafter filtration, washing and drying at100 consisted of 2.4 g. of crude Z-amino- 6-hydroxy-8-phenylpurine.

2-a'1n'ino-6-piperidino-Smhenylpurine 1"g. of crude 2 amino-6-chloro'8-phenylpurine was" refluxed with 2 -ml.-of piperidine, 5 ml; of

absolute ethanol-and 0.1 ml. of concentrated hydrochloric acid for 1 hour. The reaction mixtu're' was then diluted with 150" ml. of'water,

acidified" with hydrochloric" acid and the insoluble' residue collected. This residue consisted of i 0.5 g. of a crude 2-amino-6-piperidino-8-phenylpurine.

EXAMPLE 22 2-amino 6 thiol-8-p-chlorophenylpurine =4 g. of #crude 2-amino-6-chloro-8rp-chloro phenylpurine' and 50 ml. of. 1.8 .N sodium hydrosulfide solution were placed in a bomb and heated After cooling, the recipitate purified by solution in 200 cc. 1 N sodium hydroxide and reprecipitation with acetic acid. After drying at 110, the yield of 2-amino- 6-thiol-8 p-chlorophenylpurine was 2.1' g.

. EXAMPLE" 23 2-amino-6-methyZthio-8-p-chlorophenylpurine 1 g. of 2-amino-6-thiol-8-p-chlorophenylpurine (prepared in Example 21)"was dissolved in 10 ml. ofw'ater by addition of 4 ml. of 1.8-

N sodiumhydroxide solution. To thiSISOllltiOIl was added, withshaking,.0.45 g. of. dimethyl sul- After 10 minutes. the'pH'was adjusted'to 5 with acetic acid and the precipitate filtered ofi. This precipitate was dissolved in 85 ml..of

-boiling water containing-4 ml. of 1.8 N sodium hydroxide, filtered hot, and the filtrate acidified with'acetic acid. After cooling; filtration and drying at 110, the yield of' 2-amino-6-methyl thio-8-p chlorophenylpurine was 0.7 g.

EXAMPLE 24 2-amin0-6-morphoZino-8-p-chlorophenylpurine A mixture of 1.1 g. of crude 2-amino-6-chloro- B-p-chlorophenylpurine, 3 ml. of morpholine, 0.1

ml. of concentrated hydrochloric acid and 5 ml. "of' absolute ethanol was refluxed for one-half hour. *lutedto-IOO ml. with water. The yellow pre- The reaction mixture was cooledand dimethylamine.

.cipitate,-; after: filtration; .washing and .dryingat 110, consisted-of 0.85 g. ;.of 2ramino-fiJ-morpholino-8-p-chlorophenylpurine.

EXAMPLE 25 EXAMPLE 26 2 -amino-6-dimethyZam-ino-8-p-chlorophenylpurine A mixture of 1.1 g. crude 2-amino-6-chloro- 8-p-chlo1opheny1purine and 0.1 ml. of concentrated hydrochloric. acid in 25 ml. of 33% solution of dimethylamine in methanol was heated at 60 for 1 hour. The methanol and excess dimethylamine were boiled off in a hot water bath until the volume of the reaction mixture was 5 ml. The reaction mixture was then diluted to ml. with water,-made strongly acidic with hydrochloricacid and the precipitate collected by filtration. Theyield of 2-amino-6- dimcthylamino-8-p-chlorophenylpurine hydrochloride hemihydrate was 0.86 g.

EXAMPLE 27 2-amino-6-methylamino-8-pchlorophenylpurine 1.1 g. of crude 2-amino-6-chloro-8-p-chlorophenylpurine was dissolved by warming in 10 ml. of a 25% aqueous solution of methylamine containing 0.15 ml. of concentrated hydrochloric acid. The mixture was allowed to stand for two days at room temperature, then boiled for ca. 10 minutes to remove some of the excess The mixture was diluted'to, 100 ml. with water, made strongly acid with hydrochloric acidand the precipitate filtered off. .The

..yield'of;crude 2-amino6-methylamino-8-p-chlorophenylpurine hydrochloride was 8.85 g.

I'EXAMPLE 28 2-amino-(i=hydroxy-8-p chlorophenylpurine 1.5 g. of Crude. 2-amino-6-ch1oro-8 -p-chlorophenylpurinewas refluxed for 2 hours with 100 ml. of 2N hydrochloric acid. The mixturewas cooled and the precipitate of 2-amino-6-hydroxy- B-p-chlorophenylpurine hydrochloride filtered ofi. .JAfIt5er washing and drying at the yield was EXAMPLE 29 2,6-diaminO-B-p-chlorophenylpurine 6.2 g. .of Z-amino-6-chloro-8-p-chloropheny1- purine was heated with 75 ml. of concentrated ammonium hydroxide and 1 m1. of concentrated hydrochloric acid in a bomb at for 6 hours. The contents of the bomb were evaporated to dryness on the steam bath and the residue leached with 200 ml. of water. After filtration and drying at 110, the yield of crude 2,6-diamino-8-pchlorophenylpurine was 5.4 g.

EXAMPLE 30 2 amino 6 (bis-p-hydroryethyl)amino-8-pchlorophenylpurine A mixture of 10.2 g. of 2-amino-6-chloro-8-pchlorophenylpurine, 13 ml. of bis-fl-hydroxyethylamine 0.5 ml. of concentrated hydrochloric acid and 75 ml. of ethanol was refluxed for two hours.

, The mixture was diluted with 500 ml. of water and made acidic with hydrochloric acid. The precipitate was filtered off, dissolved in 200 ml. of 0.3 N sodium hydroxide, filtered and acidified with acetic acid. The yield of 2-amino-6-(bis-fihydroxyethyl) amino-8-p-chlorophenylpurine was 8.9 g.

EXAMPLE 31 z-amz'no-6-bromo-8-p-chlorophenylpurinc The phosphorus oxychloride was removed under reduced pressure and the residue treated with 150 g. of ice water. The precipitate was filtered off, dissolved in 100 ml. of water and 35 ml. of 2 N sodium hydroxide and reprecipitated by acidification to pH 5 with acetic acid. After filtration, washing and drying at 110, the yield of crude 2-amino 6 chloro-8-o-methylphenylpurine was 1.75 g.

EXAMPLE 33 2-amin0-6-chloro-8-m-chlorophenylpurine 12.1 g. of 2,4-diamino-5-m-chlorobenzamido-6- hydroxy-pyrimidine was refluxed for 3 hours with 250 ml. of phosphorus oxychloride. The phosphorus oxychloride was then distilled under reduced pressure and the residue treated with 250 g. of ice. Theprecipitate was filtered ofr',

dissolved in 300 ml. of 0.5 N sodium hydroxide and reprecipitated by acidification with acetic acid. After filtration, washing and drying at 1109,...

the yield of crude 2-arnino-6-chloro-8-m-chlorophenylpurine was 9.7 g.

EXAMPLE 34 2-amino-S-hydromy-8-m-chloroplrenylpurine 2 g. of crude 2-amino-6chl0ro-8-m-chlorophenylpurine was refluxed for 2 hours with 100 ml. of 2 N hydrochloric acid. The mixture was then diluted to 400 ml. with water, chilled and the precipitate of 2-amino-6-hydroxy-8-m-chlorophenylpurine hydrochloride filtered off. After washing and drying at 110, the yield was 1.55 g.

EXAMPLE 35 Z-amz'no .6 hydrazine-8-mchlorophenylpurinc A mixture of 1 g. of crude 2-amino-6-chloro- S-m-chlorophenylpurine, 5 m1. of an 85% aqueous solution ofhydrazine hydrate, 0.5 ml. of 2 N hydrochloric acid and 5 ml. of ethanol was heated in a boiling water bath for one-half hour. The reaction mixture was diluted to 100 ml. with water, brought to pH 6 with hydrochloric'acid and the precipitate filtered off. After washing and drying at 110, the precipitate of 2- 'amino- G-hydrazino-8-m-chlorophenylpurine hydrochloride was 0.8 g.

EXAMPLE 36 2-amino-6-chloro-8-o-chlorophenylpurine 6.5 g. of 2.l-diamino-5-o-chlorobenzamido-6- hydroxypyrimidine was refluxed with 200 ml. of phosphorus oxychloride for 3 hours. The phosphorus oxychloride was removed under reduced pressure and the residue treated with 250 g. of ice. The precipitate was filtered ofi, dissolved in 200 ml. of 0.5 N sodium hydroxide and reprecipitated by acidification with acetic acid. The yield of crude 2 amino-6chloro-8-o-chlorophenylpurine was 4.1 g.

EXAMPLE 3'7 Z-amino-6-hydroasy-8-o-chlorophenylpurine 2.3 g. of crude 2-amino-6-chloro-8-o-chlorophenylpurine was refluxed with 170 ml. of 2.5 N hydrochloric acid for 2 hours. The mixture was diluted to 250 ml. with water, cooled and the precipitate filtered off. The yield of crude Z-amino- 6-hydroxy-8-o-chlorophenylpurine hydrochloride was2.1g.

7 EXAMPLE as Z-amz'no-6-chZoro-8-p-carbomethomyphenylpurine 8 g. of 2,4 diamino 5 p carbomethoxybenzamido-fi-hydroxypyrimidine, prepared in the usual mannerfrom 2,51,5-triamino-fi-hydroxypyrimidine bisulfite and p-carboxymethylbenzoylchloride, was refluxed for 5 hours with 250 ml. of phosphorus oxychloride. The phosphorus oxychloride was removed under reduced pressure and the residue poured on 250 g. of ice. The precipitate was filtered off, dissolved in 375 ml. of 0.5 N sodium hydroxide and reprecipitated by acidification to pH 5 with acetic acid. After centrifugation, washing and drying at 110, the yield of crude 2-amino-6-chloro-8-p-carbomethoxyphenylpurine was 6.7 g.

EXAMPLE 39 2-ammo-6-chZ0ro-8- (2,4'-dichlorophenyl) purine 9 g. of 2,4 diamino 5 (2,4'- dichlorobenzamido)-6-hydroxypyrimidine, prepared in the usual manner from 2,4,5-triamino-6-hydroxypyrimidine and 2,4-dichlorobenzoylchloride, was refiuxed with 250 ml. of phosphorus oxychloride for 3 hours. The phosphorus oxychloride was removed under reduced pressure and the residue poured on 300 g. of crushed ice. The precipitate was filtered ofi, dissolved in 300 ml. of 0.5 N sodium hydroxide and the solution filtered into 200 ml. hot dilute acetic acid. After filtration, washing and drying at the yield of 2-amino-6- chloro-8-(2',4'-dichlorophenyl)purine was 7.2 g.

EXAMPLE 40 2--amino-6-chloro-S-p-bmmozahenylpurine 7.5 g. of' z t-diamino 5-p-bromobenzamido-6- hydroxypyrimidine, prepared in the usual manner, were refluxed with 250 ml. of phosphorus oxy- We claim:

1. As a new compound a 2,6-diamino-8-ary1- purine the aryl group having a maximum of two rings.

2. As a new compound a 2-amino-6-substituted ainino-8-arylpurine the aryl group having a maximum of two rings.

3. As a new compound a 2-amino-6-thio1-8- arylpurine the aryl group having a maximum of two rings.

4. 2,6-dianiino-8-p-ch1oropheny1purine.

5. 2 amino 6 hydroxy 8 p chlorophenylpurine.

6. 2 amino 6 methylamino 3 p chlorophenylpurine.

7. 2 amino 6 piperidino 8 p chlorophenylpurine.

8. 2-amino-6-chloro-3-phenylpurine. 9. As a new compound a 2-amino-8-arylpurine having the following formula:

where M is an aryl radical selected from the class consisting of phenyl and naphthyl, Z is a substituent selected from the class consisting of chlorine, bromine, hydroxyl, amino, alkylamino, dialkylamino, arylamino, alkylarylamino, hy-

drazino, thiol, alkylthio, the N-morpholino and N-piperidino radicals bound to the 6 position through the nitrogen atom, and where X is a radical selected from the class consisting of hydrogen, amino, chlorine, bromine, lower alkyl and alkoxyl and Y is selected from the group comprising hydrogen, amino, chlorine, bromine, lower alkyl and alkoxyl, carboxy, carbalkoxy and carbamido.

10. The process of forming S-phenylpurine derivaties which comprises preparing a 2,4-diamino-ii-benzamido pyrimidine, heating the product to its melting point and recovering the s-phenylpurine derivative from the reaction product.

11. The process of forming 8-pheny1purine derivaties which comprises preparing a 2,4-diamino-E-benzamido pyrimidine and heating the product in the presence of phosphorylchloride to produce the corresponding S-phenylpurine.

12. The process of forming a-naphthylpurine derivatives which comprises preparing a 2,4-diamino-5-naphthoylamino pyrimidine, heating the product to its melting point and recovering the S-naphthylpurine derivative from the reaction product.

GEORGE H. I-HTCHINGS. GERTRUDE B. ELION.

No references cited. 

9. AS A NEW COMPOUND A 2-AMINO-8-ARYLPURINE HAVING THE FOLLOWING FORMULA:
 10. THE PROCESS OF FORMING 8-PHENYLPURINE DERIVATIES WHICH COMPRISES PREPARING A 2,4-DIAMINO-5- BENZAMIDO PYRIMIDINE, HEATING THE PRODUCT TO ITS MELTING POINT AND RECOVERING THE 8-PHENYLPURINE DERIVATIVE FROM THE REACTION PRODUCT. 